EZH2 deletion does not impact acinar regeneration but restricts progression to pancreatic cancer in mice

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Abstract

Enhancer of Zeste Homologue 2 (EZH2) is part of the Polycomb Repressor Complex 2, which promotes trimethylation of lysine 27 on histone 3 (H3K27me3) and genes repression. EZH2 is overexpressed in many cancers and studies in mice attributed both pro-oncogenic and tumor suppressive functions to EZH2 in pancreatic ductal adenocarcinoma (PDAC). EZH2 deletion enhances de novo KRAS-driven neoplasia following pancreatic injury, while increased EZH2 expression in PDAC patients is correlated to poor prognosis, suggesting a context-dependant effect for EZH2 in PDAC progression. In this study, we examined EZH2 in pre- and early neoplastic stages of PDAC. Using an inducible model to delete the SET domain of EZH2 in adult acinar cells (EZH2∆SET), we showed loss of EZH2 activity did not prevent acinar cell regeneration in the absence of oncogenic KRAS (KRASG12D), nor increase PanIN formation following KRASG12D activation in adult mice. Loss of EZH2 did reduce recruitment of inflammatory cells and, when combined with a more aggressive PDAC model, promoted widespread PDAC progression and remodeling of the tumor microenvironment. This study suggests expression of EZH2 in adult acinar cells restricts PDAC initiation and progression by affecting both the tumour microenvironment and acinar cell differentiation.

Authors

Emilie Jaune-Pons, Xiaoyi Wang, Fatemeh Mousavi, Zachary Klassen, Abdessamad Elkaoutari, Kurt Berger, Charis Johnson, Mickenzie B. Martin, Saloni Aggarwal, Sukhman Brar, Muhammad Khalid, Joanna F. Ryan, Parisa Shooshtari, Angela J. Mathison, Nelson Dusetti, Raul Urrutia, Gwen Lomberk, Christopher L. Pin